Antibody-drug conjugates are a class of therapeutics that connect an antibody to a drug via a linker. The antibody serves as a drug delivery system to a cell expressing an antigen recognized by the antibody. Linkers such as poly-1-hydroxymethylethylene hydroxymethyl formal (“PHF”) have been used in this type of drug delivery system. Highly hydrophilic polyacetal-based PHF polymers can be utilized as a linker to attach multiple hydrophobic drugs to the antibody without affecting the physicochemical properties of the antibody or drug. However, existing PHF-based linkers have significant limitations.
In known PHF-based linkers, drugs or small molecules are attached to the PHF backbone through the acylation of hydroxyl groups on the PHF resulting in ester linkages at the acylation sites. Such PHF-based drugs or small molecules are disclosed in U.S. Pat. No. 8,685,383, hereby incorporated by reference in its entirety. However, these newly formed ester linkage can undergo enzymatic cleavage upon administration to a subject. Additionally, these ester linkages are also cleaved under basic conditions. Moreover, existing PHF-based technology utilizes a second cleavable ester linkage, in addition to the ester linkage of hydroxyl groups on PHF resulting in two enzymatically cleavable sites complicating various mechanistic processes for the compounds. Multiple enzymatically cleavable sites on the linker of antibodydrug conjugates may decrease antitumor activity and increase the risk of toxicity due to premature and nontargeted release of the drug from the antibody. Such premature release may narrow the therapeutic window. Moreover, multiple cleavable sites generally make pharmacokinetics studies more challenging due to more complex kinetic action occurring in linked compounds. Accordingly, delivery of drug payloads with ester linkers can thus be unreliable and difficult to reproduce.
Thus, there is a need in the art to identify non-cleavable linkers that serve as effective antibody-drug conjugates to deliver drugs in a reliable and reproducible manner. The presently disclosed linkers and methods meet this need.